fisiopatologia del metabolismo del ferro e implicazioni ... · fisiopatologia del metabolismo del...

DG - 1PBM Ovest Milanese 16 Febbraio 2018

Fisiopatologia del metabolismo del ferro e implicazioni terapeutiche

Domenico GirelliDipartimento di Medicina, Università di Verona

Centro di Riferimento per i Disordini del Metabolismo del FerroEuroBloodNet (European Reference Network for Rare Hematological Diseases)

anemianeuromuscolar impairment

iron overloadtoxic organ damage

low excess

Iron: essential but potentially dangerous

easily exchange electronsFe3+ ↔ Fe2+

useful redox properties

key-component of enzymes crucial for O2 transport and

energy production (Hb, cytochromes…)

free radicals generation (Fe2++ H202 → Fe3+ + OH- + OH•)

strict regulation of body iron content needed


THE HEPCIDIN-FERROPORTIN AXIS

Ganz T, Physiol Rev 2013

• Hepcidin: small peptide mainly produced by the liver

• interact with its receptor(Ferroportin, the only known iron exporter from the cells, ubiquitous but highly expressed in duodenal cells, macrophages, hepatocytes)

Kushner JP, Blood 2010


Systemic “ecological” iron homeostasis

≈2 g

≈600 mg

Erythroid precursors in Bone Marrow

Fe3+

Fe3+

Fe3+

FERROPORTIN

Splenic macrophages

Circulating RBCsPlasma Transferrin 30%

losses (1-2 mg/day)mucosal exfoliation,

menses

duodenal absorption

(1-2 mg/day)

enterocytes

intestinal lumenFe3+

Fe3+FERROPORTIN Girelli D, Int J Hematol 2018

Liver 300-1000 mg

hepcidin

_

_

200 billion new RBCs/day (2.4 million/sec)


Clinical conditions influencing serum hepcidin levels

Girelli D, Blood 2016


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Anemia (and Iron Deficiency): one of most frequent disease worldwide

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Kassebaum N, Hematol Oncol Clin N Am 2016

- 27% of world’s population is affected by anemia

- Iron Deficiency ( ) = dominant cause (≥60%)

- Mainly due to socio-economic reasons

(but iron replacement therapy not always easy as it seems)

PBM Ovest Milanese 16 Febbraio 2018

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Oral iron therapy: the frontline of IDA treatmentCNS dysfunction

heart dysfunction

Muscle weakness

Restless legs Synd.

Pica

Normal Iron Deficiency Anemia

Effective Inexpensive

GI AEs (35-59%) → non-adherence common

BUTLESS THAN IDEAL:


Moretti D, Blood 2015


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Oral iron therapy: the frontline of IDA treatmentCNS dysfunction

heart dysfunction

Muscle weakness

Restless legs Synd.

Pica

Normal Iron Deficiency Anemia

Effective Inexpensive

GI AEs (35-59%) → non-adherence common

BUTLESS THAN IDEAL:

Need of prolonged administration (3 months for replacing iron stores)Poorly absorbed in certain conditions


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Different pharmacokinetic between oral and IV iron, revisited in the hepcidin era

Erythroid precursors in Bone Marrow

Fe3+

Fe3+

ferroportin

Splenic macrophages

Circulating RBCs

Plasma transferrin

Oral Fe

IVFe/carbohydrate

complexes

Mucosal integrityrequired

↓ pH

ferroportin

Fe3+

unabsorbed Fe3+ (AEs)

↑ /N sufficient to block

hepcidin

hepcidin

↑ /N not sufficient to block (only ↑↑↑levels as in sepsis/acute inflammation)

Girelli D, Int J Hematol 2018


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Established indications to i.v. ironcondition examples/commentsFailure of oral iron non-adherence, AEs Malabsorption celiac disease, gastritis

(atrophic, autoimmune, Hp+), bariatric surgery, genetic IRIDA

Severe IDA generally accepted threshold: Hb < 8 g/dl

End-stage Chronic Kidney Disease (CKD)

(+ ESAs)

Inflammatory Bowel Diseases IDA in active diseasePregnancy severe IDA in II-III trimester Heart Failure (HF)* Systolic HF (LVEF ≤ 45%)

*Iron deficiency (even without anemia): serum ferritin <100 µg/L or <300 µg/L, if TSAT ≤20%Camaschella C, NEJM 2015 (adapted)


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i.v. iron: historical (and chemical perspective)

human ferritin1947: Fe-Saccharide

1954: Fe-Dextran(HMW)

1991: Fe-Dextran(LMW)

1999: Fe-Gluconate

2000: Fe-Sucrose

>2009: FerumoxytolFe-isomaltoside

Fe-Carboymaltose

“New”

8-25

nm

Fe3+

oxyhydroxide

(polynuclear CORE)

carbohydrate shell(stabilizer)

unique for each compound

Key differences in: Immunogenicity Strength of stabilization

His

tory

of i

.v. i

ron

risk

risk

risk

Girelli D, Int J Hematol 2018


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HMW dextran: the only truly immunogenic i.v. iron drug

1954: Fe-Dextran(HMW)

IgE

Anaphylaxis

Retrospective analysis of > 30 million doses of i.v. iron: virtually all life-threatening AEs by i.v. iron are due to HMW-dextranCerthow GM, Nephrol Dial Transplant 2006

definitively removed form the marketPBM Ovest Milanese 16 Febbraio 2018

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Other mechanism(s) for i.v. iron SAEs

Szebeni J, Br J Pharmacol 2105

Complement activation-related pseudo-allergy


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Meta-analysis of 103 trials using non-HMW-dextran iron

Serious AEs can occur with any preparation but are no more frequent than comparators, and extremely rare <1:200,000 doses (major transfusional reactions = 1:21,000).

Avni T, Mayo Clin Proc 2015

(LMW)

)

Only minor infusion reactions consistently reported


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Minor infusion reactions

≈1:200

Flushing ± myalgias (chest or lumbar) ± nausea ± nasal congestion without sustained hypotension

Almost invariably self-limited

Can be aggravated by treatment with antihistamines (do not treat)

Do not recur with re-challenge

Auerbach M, Hematology 2016

5 min, no intervention Macdougall IC, Kidney Int 2016


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Stability of i.v. iron/complex is crucial for infusion reactions

Stable complex


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Stability of i.v. iron/complex is crucial for infusion reactions

Fe3+

Fe3+

Fe3+

Fe3+

Fe3+

Unstable complex

Release of free iron in plasma before phagocytosis

Acute hemodynamic toxicity

Auerbach M, Hematology 2016

ErythemaFlushingHypotension(not sustained)

Amount of released free iron is dose-dependent → poor stability limits the total dose of elemental iron that can be safely administered per single infusion


Currently used i.v. iron preparationsDrug Brand name Stability Maximum

single doseTotal

replacement dose in single

infusion (1-1,5 g)

Minimunadministration

time

Fe-Gluconate Ferlixit® low 125 mg no(repeated access

needed)

30-60 min

Fe-Sucrose Venofer® low-moderate 200 mg no(idem)

30 min

Fe-Carboxymaltose Ferinject® high 1000 mg yes 15 min

Fe-isomaltoside Monofer® high 20 mg Fe/Kg yes 15 min

Ferumoxytol Feraheme® high 510 mg yes/no 15 min

“Third generation”


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Ganzoni’s formula and simplified schemes

https://www.easycalculation.com/medical/iron-deficit-calculator.php

When using FCM

validated on Evstatiev R, Gastroenterology 2011


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Extended indications for i.v. iron

condition examples/commentsID/IDA in elderly If comorbidities/polypharmacy

(including PPI) prevent adherence to (or effectiveness of) long-term oral iron

Perioperative anemia Patient Blood Management strategies to prevent RBCs transfusions

IDA in cancer ± ESAs Restless leg syndrome*Mountain Sickness* (prevention)Heavy Uterine Bleeding*

* Auerbach M, Hematology 2016 (adapted)


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Take-home messages

New (“third generation”) i.v. iron drugs are characterized by higher stability of the carbohydrate shell and by improved safety profiles

They allow easy and convenient schedules, with complete replacement of iron in 1 or 2 administrations.

This drives a paradigm shift in the treatment of one of the most common disease worldwide, with extending indications (to be confirmed).


The Verona Interdisciplinary Group on Iron Disorders

Participants Units1. Internal Medicine2. Clinical Chemistry & Molecular Biology3. Blood Bank / Transfusional Service4. Radiology5. Pathology6. Gastroenterology

http://www.gimferverona.org

Fabiana Busti, Paola Capelli, Annalisa Castagna, Michela Corbella, Massimo Delledonne, Giorgio Gandini, Alejandro Giorgetti, Giacomo Marchi, Oliviero Olivieri, Roberto Pozzi-Mucelli, Monica Rizzi, Alice Vianello, Luciano Xumerle.


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